In general, the present invention relates to pharmaceutical compositions, and more particularly, to pharmaceutical compositions for the treatment of diabetes mellitus using combination therapy.
Diabetes mellitus is a term generally used to refer to various pathological states characterized by hyperglycemia and altered metabolism of lipids, carbohydrates and proteins. These conditions are also often associated with other co-morbidities, such as obesity and an increased risk of cardiovascular disease. By some estimates, as many as 600,000 new individuals become clinically diabetic every year in the United States.
Diabetic conditions are generally classified as either insulin-dependent diabetes mellitus (IDDM, Type I diabetes) or non-insulin-dependent diabetes mellitus (NIDDM, Type II diabetes). There are also less common clinical pathologies that are associated with diabetic conditions, such as gestational maturity-onset diabetes of youth (MODY), tropical diabetes secondary to chronic pancreatis, diabetes secondary to pancreatic disease or surgery, and diabetes secondary to endocrinopathies.
Virtually all forms of diabetes are due to a decrease in the circulating concentration of insulin (insulin deficiency) and/or a decrease in the response of peripheral tissues to insulin (insulin resistance). These abnormalities lead to alterations in the metabolism of carbohydrates, lipids, ketones and amino acids, and a hyperglycemic condition. IDDM appears to have an autoimmune etiology, which results in destruction of xcex2 islet cells in the pancreas and the resulting inability to produce insulin. The etiology of NIDDM, the most prevalent form of diabetes, is more complex and possibly heterogeneous. Some loss of xcex2-cell volume is generally noted in these patients, as well as decreased circulating levels of insulin. NIDDM patients may also suffer commonly from insulin resistance.
The best-established therapy for all IDDM and many NIDDM patients is subcutaneous insulin treatment. Additionally, insulin is used as the treatment of choice for patients with postpancreatectomy diabetes or gestational diabetes. While insulin is a key element in the control of these hyperglycemic conditions, there are a number of limitations associated with its use, including hypoglycemia, allergic reactions to insulin, lipoatrophy, lipohypertrophy, body weight gain, edema, and insulin resistance. There are a number of new forms of insulin on the market or in various stages of clinical evaluation, including new delivery systems, various recombinant forms, new routes of administration, and gene therapy. These novel forms of insulin treatments are believed to share some of the same limitations outlined above. A significant improvement in the treatment of diabetes can be achieved if insulin treatment is combined with agents that increase the insulin sensitivity of the peripheral tissues.
The concept of combination therapy is well exploited in current medical practice. Treatment of a pathology by combining two or more agents that target the same pathogen or biochemical pathway sometimes results in greater efficacy and diminished side effects relative to the use of the therapeutically relevant dose of each agent alone. In some cases, the efficacy of the drug combination is additive (the efficacy of the combination is approximately equal to the sum of the effects of each drug alone), but in other cases the effect can be synergistic (the efficacy of the combination is greater than the sum of the effects of each drug given alone). In real medical practice, it is often quite difficult to determine if drug combinations are additive or synergistic.
For most diabetic patients, treatment involves some form of insulin therapy. In addition, IDDM patients may receive a biguanide (e.g., metformin) to enhance the insulin utilization by peripheral tissues. NIDDM patients are often treated with a combination of insulin, a sulfonylurea (to enhance insulin production in the pancreas) and a biguanide or glitazone (to enhance insulin sensitivity by peripheral tissues). For example, the improved utility of a glitazone in combination with a sulfonylurea was recently demonstrated in human clinical trials (see, WO 98/36755). Recently, two glitazone compounds (rosiglitazone and pioglitazone) were approved in the United States for the treatment of NIDDM patients in combination with metformin.
A variety of antidiabetic compounds are known. For example, sulfonylureas are a group of drugs that induce hypoglycemia by stimulating insulin release from the pancreas. Generally, sulfonylureas have found wide utility in the treatment of NIDDM. Their efficacy is decreased in IDDM because of the inherent inability of the patient to produce insulin. Adverse reactions to sulfonylureas occur in a fraction of patients, particularly the elderly. One of the most severe side effects is hypoglycemia and coma. Other side effects include nausea and vomiting, cholestatic jaundice, agranulocytosis, cardiovascular mortality, aplastic and hemolytic anemias, generalized hypersensitivity reactions and dermatological reactions.
Biguanides are another group of drugs, first introduced in the mid 1950""s, that have shown efficacy in the treatment of hyperglycemia by mechanisms that are not well understood. The best known agents of this type include metformin, phenformin and buformin. Unlike the sulfonylureas, metformin does not induce release of insulin from the pancreas. It is thought that its effects are mediated by increasing insulin activity in peripheral tissues, reducing hepatic glucose output due to inhibition of gluconeogenesis and reducing the absorption of glucose from the intestine. Side effects associated with the use of biguanides include lactic acidosis, diarrhea, nausea, and anorexia. These agents are often given in combination with drugs that increase the output of insulin from the pancreas, such as the sulfonylureas, which sometimes results in greater efficacy and/or the ability to use lower doses of the drugs, with an improved side effect profile.
More recently, the glitazones have been introduced and are widely used in the treatment of NIDDM. These agents, also known generically as thiazolidinediones, such as troglitazone, rosiglitazone and pioglitazone, are thought to work by increasing the sensitivity of peripheral tissues, such as skeletal muscle, towards insulin. They are often used in combination with insulin or other agents, such as the sulfonylureas, that enhance the release of insulin from the pancreas. A number of side effects have been described during the clinical evaluation of these agents, including hepatotoxicity, organomegaly, edema, anemia and body weight gain. While hepatotoxicity may be the most acutely life-threatening of these conditions, it does not appear in a large percentage of the patient population. On the other hand, the increases in body weight gain associated with chronic glitazone treatment are generally perceived as worsening an already critical co-morbid condition in the majority of the diabetic patients, and may ultimately result in the loss of antidiabetic efficacy for this type of agent after chronic treatment.
xcex1-Glucosidase inhibitors, such as acarbose, reduce intestinal absorption of starch, dextrin, and disaccharides by inhibiting the action of intestinal brush border xcex1-glucosidase. Inhibition of this enzyme slows the absorption of carbohydrates and the rise in plasma glucose that normally follows after a meal is blunted. Acarbose has shown some benefit in IDDM and NIDDM patients, but is often associated with dose-related malabsorption, flatulence and abdominal bloating.
Other types of agents that have found limited utility in treating diabetes include potassium channel antagonists such as repaglinide, and aldose reductase inhibitors such as zopolrestat and tolrestat. Still in the experimental stage, glucagon antagonists, activators of the retinoid-X receptor (RXR), activators of PPARxcex1, activators of PPARxcex4 and anti-obesity agents are also being evaluated as potential antidiabetic agents.
In view of the foregoing, there remains a need in the art to provide more efficacious treatment for diabetic conditions and diabetic complications. Combination therapy treatments are needed that will reduce the amount of drugs taken, thereby decreasing side effects. The present invention fulfills these and other needs.
The present invention provides pharmaceutical compositions for the treatment of a variety of diseases, including diabetes mellitus, such as IDDM, NIDDM, gestational diabetes, juvenile diabetes, and the like, using combination therapy. In certain aspects, the pharmaceutical compositions comprise a pharmaceutically acceptable carrier with a compound of Formula I and an antidiabetic agent. Advantageously, the compositions of the present invention provide clinical advantage over the use of a single agent alone. As such, the present invention provides a composition comprising:
i) a compound of Formula I 
wherein
Ar1 is an aryl group; X is a divalent linkage selected from (C1-C6)alkylene, (C1-C6)alkylenoxy, (C1-C6)alkylenamino, (C1-C6)alkylene-S(O)kxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R11)xe2x80x94, xe2x80x94N(R11)C(O)xe2x80x94, xe2x80x94S(O)kxe2x80x94 and a single bond, wherein R11 is a member selected from hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl and aryl(C1-C4)alkyl; and the subscript k is an integer of from 0 to 2; Y is a divalent linkage selected from alkylene, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(R12)xe2x80x94S(O)mxe2x80x94, xe2x80x94N(R12)xe2x80x94S(O)mxe2x80x94N(R13)xe2x80x94, xe2x80x94N(R12)C(O)xe2x80x94, xe2x80x94S(O)nxe2x80x94 and a single bond, wherein R12 and R13 are members independently selected from hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl and aryl(C1-C4)alkyl; and the subscripts m and n are independently integers of from 0 to 2;
R1 is a member selected from the group hydrogen, heteroalkyl, aryl, arylalkyl, halogen, cyano, nitro, (C1-C8)alkyl, (C1-C8)alkoxy, xe2x80x94C(O)R14, xe2x80x94CO2R14xe2x80x94C(O)NR15R16, xe2x80x94S(O)pxe2x80x94R14, xe2x80x94(S)qxe2x80x94NR15R16, xe2x80x94Oxe2x80x94C(O)xe2x80x94OR17, xe2x80x94Oxe2x80x94C(O)xe2x80x94R17, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94NR15R16, xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17 and xe2x80x94N(R14)xe2x80x94C(O)xe2x80x94R17; wherein
R14 is a member selected from hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl;
R15 and R16 are members independently selected from hydrogen, (C1-C8)alkyl, (C1 -C8)heteroalkyl, aryl, and aryl(C1-C4)alkyl, or taken together with the nitrogen to which each is attached form a 5-, 6- or 7-membered ring;
R17 is a member selected from alkyl, heteroalkyl, aryl and arylalkyl;
the subscript p is an integer of from 0 to 3;
the subscript q is an integer of from 1 to 2;
R2 is a member selected from(C1-C8)alkyl, (C1-C8)heteroalkyl, aryl and aryl(C1-C4)alkyl;
R3 is a member selected from hydrogen, halogen, cyano, nitro, (C1-C8)alkyl and (C1-C8)alkoxy;
including pharmaceutically acceptable salts of compounds of Formula I; and
ii) one or more antidiabetic agents, including, but not limited to, sulfonylureas, biguanides, glitazones and other PPARxcex3 agonists, PPARxcex1 agonists, PPARxcex4 agonists, xcex1-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, insulin therapy or other anti-obesity agent (5), prodrugs thereof, or pharmaceutically acceptable salts of the antidiabetic agents, and a pharmaceutically acceptable carrier or diluent.
In certain aspects, the compositions of the present invention comprise a compound of Formula I formulated together with one or more antidiabetic agents. Alternatively, the compositions of the present invention comprise a compound of Formula I independently formulated with one or more antidiabetic agents i.e., separately formulated.
Suitable antidiabetic agents include, but are not limited to, sulfonylureas, biguanides, glitazones and other PPARxcex3 agonists, xcex1-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, activators of RXR, activators of PPARxcex1, activators of PPARxcex4, insulin therapy or other anti-obesity agents. The administration of a composition comprising i) a compound of Formula I, which are PPARxcex3 modulators and known to increase peripheral tissue sensitivity to insulin, with ii) an antidiabetic agent such as insulin therapy, or a stimulator of insulin secretion, and the like, increases the efficacy of either agent alone. In addition to increased efficacy, the combination therapy of the present invention allows for a concomitant reduction in the dose of the agents. The combination therapy of a compound of Formula I and one or more of another antidiabetic agents (e.g., biguanides, glitazones, RXR ligands, PPARxcex3 agonists, etc.) results in a reduction in the side effects normally associated with certain antidiabetic agents.
In certain aspects, compounds of Formula I are administered in combination with antidiabetic agents that are ineffective for stimulation of insulin secretion or insulin sensitivity, such as a-glucosidase inhibitors, potassium channel antagonists, aldose reductase inhibitors, glucagon antagonists, RXR ligands, PPARxcex1 agonists, PPARxcex4 agonists, and anti-obesity agents. Surprisingly, these types of combination therapy result in enhanced efficacy relative to the use of the single agents alone.
In another embodiment, the present invention provides methods of treating metabolic or inflammatory disorders in a host by administering a composition of the present invention. In certain preferred aspects, the method includes the administration of a composition comprising a combination of a compound of Formula I with the antidiabetic agent delivered in a simultaneous manner, such as in a single formulation. In certain other aspects, the methods of the present invention include combination therapy wherein the compound of Formula I is administered first in one formulation, followed by the antidiabetic agent in a separate formulation. The methods also include an antidiabetic agent being delivered first in one formulation, followed by a compound of Formula I in a separate formulation. The present invention includes all such methods of administration. The combination therapy is especially efficacious on conditions associated with diabetes, such as obesity, cardiovascular disease, hypercholesterolemia and other lipid disorders, peripheral neuropathies and other neurological disorders, and the like.
These and other feature and advantages will become more apparent when read with the accompanying Figures and detailed description that follow.
The term xe2x80x9calkyl,xe2x80x9d by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)ethyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. The term xe2x80x9calkyl,xe2x80x9d unless otherwise noted, is also meant to include those derivatives of alkyl defined in more detail below as xe2x80x9cheteroalkyl,xe2x80x9d xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9calkylene.xe2x80x9d The term xe2x80x9calkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by xe2x80x94CH2CH2CH2CH2xe2x80x94. Typically, an alkyl group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A xe2x80x9clower alkylxe2x80x9d or xe2x80x9clower alkylenexe2x80x9d is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. An alkanoyl is a RCOxe2x80x94 group.
The term xe2x80x9cheteroalkyl,xe2x80x9d by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quarternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. The heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. Examples include xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94NHxe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94N(CH3)xe2x80x94CH3, xe2x80x94CH2xe2x80x94Sxe2x80x94CH2xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)xe2x80x94CH3, xe2x80x94CH2xe2x80x94CH2xe2x80x94S(O)2xe2x80x94CH3, xe2x80x94CHxe2x95x90CHxe2x80x94Oxe2x80x94CH3, xe2x80x94Si(CH3)3, xe2x80x94CH2xe2x80x94xe2x95x90Nxe2x80x94OCH3, and xe2x80x94CHxe2x95x90CHxe2x80x94N(CH3)xe2x80x94CH3. Up to two heteroatoms may be consecutive, such as, for example, xe2x80x94CH2NHxe2x80x94OCH3 and xe2x80x94CH2xe2x80x94Oxe2x80x94Si(CH3)3. Also included in the term xe2x80x9cheteroalkylxe2x80x9d are those radicals described in more detail below as xe2x80x9cheteroalkylenexe2x80x9d and xe2x80x9cheterocycloalkyl.xe2x80x9d The term xe2x80x9cheteroalkylenexe2x80x9d by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by xe2x80x94CH2xe2x80x94CH2xe2x80x94Sxe2x80x94CH2CH2xe2x80x94 and xe2x80x94CH2xe2x80x94Sxe2x80x94H2xe2x80x94CH2xe2x80x94NHxe2x80x94CH2xe2x80x94. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
The terms xe2x80x9ccycloalkylxe2x80x9d and xe2x80x9cheterocycloalkylxe2x80x9d, by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of xe2x80x9calkylxe2x80x9d and xe2x80x9cheteroalkylxe2x80x9d, respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogen,xe2x80x9d by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as xe2x80x9cfluoroalkyl,xe2x80x9d are meant to include monofluoroalkyl and polyfluoroalkyl.
The term xe2x80x9caryl,xe2x80x9d employed alone or in combination with other terms (e.g., aryloxy, arylthioxy, arylalkyl, aroyl (ArCO), heteroaroyl) means, unless otherwise stated, an aromatic substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The rings may each contain from zero to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quarternized. The aryl groups that contain heteroatoms may be referred to as xe2x80x9cheteroarylxe2x80x9d and can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl groups include aminobenzoheteroazolyl, 2-azanaphthalenyl, bezoxazolyl, phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, 6-quinolyl, thiobenzoxazolyl, thiobenzothiazolyl and thiobenzimidazolyl. Substituents for each of the above noted aryl ring systems are selected from the group of acceptable substituents described below. The term xe2x80x9carylalkylxe2x80x9d is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) or a heteroalkyl group (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).
Each of the above terms (e.g., xe2x80x9calkyl,xe2x80x9d xe2x80x9cheteroalkylxe2x80x9d and xe2x80x9carylxe2x80x9d) are meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be a variety of groups selected from: xe2x80x94ORxe2x80x2, xe2x95x90O, xe2x95x90NRxe2x80x2, xe2x95x90Nxe2x80x94ORxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94halogen, xe2x80x94SiRxe2x80x2Rxe2x80x3Rxe2x80x3xe2x80x2, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94C(O)Rxe2x80x2, xe2x80x94CO2Rxe2x80x2, CONHRxe2x80x2Rxe2x80x3, xe2x80x94OC(O)NRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)xe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)NRxe2x80x3Rxe2x80x3xe2x80x2, xe2x80x94NRxe2x80x3C(O)2Rxe2x80x2, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NH, xe2x80x94NRxe2x80x2C(NH2)xe2x95x90NH, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)Rxe2x80x2, S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, xe2x80x94CN and xe2x80x94NO2 in a number ranging from zero to (2N+1), where N is the total number of carbon atoms in such radical. Rxe2x80x2, Rxe2x80x3 and Rxe2x80x3xe2x80x2 each independently refer to hydrogen, unsubstituted(C1-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, or aryl-(C1-C4)alkyl groups. When Rxe2x80x2 and Rxe2x80x3 are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. For example, xe2x80x94NRxe2x80x2Rxe2x80x3 is meant to include 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term xe2x80x9calkylxe2x80x9d is meant to include groups such as haloalkyl (e.g., xe2x80x94CF3 and xe2x80x94CH2CF3) and acyl (e.g., xe2x80x94C(O)CH3, xe2x80x94C(O)CF3, xe2x80x94C(O)CH2OCH3, and the like).
Similarly, substituents for the aryl groups are varied and are selected from:
halogen, xe2x80x94ORxe2x80x2, xe2x80x94OC(O)Rxe2x80x2, xe2x80x94NRxe2x80x2Rxe2x80x3, xe2x80x94SRxe2x80x2, xe2x80x94Rxe2x80x2, xe2x80x94CN, xe2x80x94NO2xe2x80x94 xe2x80x94CO2Rxe2x80x2, xe2x80x94CONRxe2x80x2Rxe2x80x3, xe2x80x94C(O)Rxe2x80x2, xe2x80x94OC(O)NRxe2x80x2Rxe2x80x3, xe2x80x94NRxe2x80x3C(O)Rxe2x80x2, xe2x80x94NRxe2x80x3C(O)2Rxe2x80x2, xe2x80x94NRxe2x80x2xe2x80x94C(O)NRxe2x80x3Rxe2x80x3xe2x80x2, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NH, xe2x80x94NRxe2x80x2C(NH2)xe2x95x90NH, xe2x80x94NHxe2x80x94C(NH2)xe2x95x90NRxe2x80x2, xe2x80x94S(O)Rxe2x80x2, xe2x80x94S(O)2Rxe2x80x2, xe2x80x94S(O)2NRxe2x80x2Rxe2x80x3, xe2x80x94N3, xe2x80x94CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where Rxe2x80x2, Rxe2x80x3 and Rxe2x80x3xe2x80x2 are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl, (unsubstituted aryl)-(C1-C4)alkyl, and (unsubstituted aryl)oxy-(C1-C4)alkyl.
Two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94Txe2x80x94C(O)xe2x80x94(CH2)qxe2x80x94Uxe2x80x94 wherein T and U are independently xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2xe2x80x94 or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94Axe2x80x94(CH2)rxe2x80x94Bxe2x80x94, wherein A and B are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, xe2x80x94S(O)2NRxe2x80x2xe2x80x94 or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl ring may optionally be replaced with a substituent of the formula xe2x80x94(CH2)sxe2x80x94Xxe2x80x94(CH2)txe2x80x94, where s and t are independently integers of from 0 to 3, and X is xe2x80x94Oxe2x80x94, xe2x80x94NRxe2x80x2xe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O)2xe2x80x94, or xe2x80x94S(O)2NRxe2x80x2xe2x80x94. The substituent Rxe2x80x2 in xe2x80x94NRxe2x80x2xe2x80x94 and xe2x80x94S(O)2NRxe2x80x2xe2x80x94 is selected from hydrogen or unsubstituted (C1-C6)alkyl.
In certain instances, aryl means two aryl groups joined by a heteroatom. These groups include diphenyl ether, phenoxy substituted 2-azanaphthalene, phenyl-thiobenzothiazole, phenyl-heterobenzoxazoles, phenyl-thiobenzoimidazoles and phenyl-heterobenzoheteroazoles (see structures IIa-IIf below).
As used herein, the term xe2x80x9cheteroatomxe2x80x9d is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al., xe2x80x9cPharmaceutical Saltsxe2x80x9d, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds that are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
The compounds of the present invention can also contain unnatural proportions of atomic isotopes, stable isotopes etc., at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I) or carbon-14 (14C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
The term xe2x80x9cprodrugxe2x80x9d refers to compounds that are drug precursors, which, following administration, release the drug in vivo via a chemical or physiological process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
xe2x80x9cA combination amount sufficient,xe2x80x9d xe2x80x9can effective combination amountxe2x80x9d xe2x80x9ctherapeutically effective combination amountxe2x80x9d or xe2x80x9can effective amount of the combination ofxe2x80x9d all refer to a combined amount of both a compound of Formula I and the antidiabetic agent that is effective to ameliorate symptoms associated with diabetic diseases. As used herein, the term xe2x80x9ccombinationxe2x80x9d of compound of Formula I with an antidiabetic agent means the two compounds can be delivered in a simultaneous manner, in combination therapy wherein the compound of Formula I is administered first, followed by the antidiabetic agent, as well as wherein the antidiabetic agent is delivered first, followed by a compound of Formula I. The desired result can be either a subjective relief of a symptom(s) or an objectively identifiable improvement in the recipient of the dosage.
The terms xe2x80x9csynergistic effective amountxe2x80x9d refers to a combined amount of both a compound of Formula I and an antidiabetic agent that is effective to cause a synergistic effect. Synergy is a biological phenomenon in which the effectiveness of two active components in a mixture is more than additive, i.e., the effectiveness is greater than the equivalent concentration of either component alone. In certain aspects, the effectiveness of the combination therapy of a compound of Formula I and an antidiabetic agent is synergistic. Thus, synergism is a result, or function, that is more than the sum of the results, or functions of individual elements.
The term xe2x80x9csimultaneous mannerxe2x80x9d and xe2x80x9ccombination treatmentxe2x80x9d refer to an administration protocol wherein the compound of the present invention and at least one antidiabetic agent are administered within a single 24-hour period.